Cardiovascular disease (CVD) is the most important complication of diabetes and chronically elevated glucose levels (hyperglycemia) are the defining feature of diabetes. We hypothesize that hyperglycemia is independently associated with CVD risk in diabetes and that this association may be partly explained by the formation of advanced glycation end products (AGEs). The candidate's long-term goal is to understand the role that hyperglycemia plays in the development of CVD in diabetes. The proposed K01 award has two primary goals: 1) to clarify progression of glycemia and how it relates to clinical and subclinical CVD in order to identify persons at high risk for development of diabetes and identify diabetics at highest risk for development of CVD and 2) to determine whether AGEs are useful population-based predictors of diabetic complications and may explain the association of hyperglycemia with CVD. The specific aims are: 1) To characterize the shape of the dose-response curves, identify thresholds, and compare the strengths of the associations for different measures of glycemia (hemoglobin A1c and fasting glucose), and the risk of diabetes, clinical CVD events, and subclinical CVD;2) To identify circulating serum markers of AGEs appropriate for conducting population-based studies of diabetic-atherosclerotic disease;and 3) to determine if serum AGEs are associated with MRI-defined carotid atherosclerosis and arterial stiffness in persons with diabetes in the Atherosclerosis Risk in Communities MRI (ARIC MRI) Study. To accomplish these Aims 1 and 3, the candidate will conduct a series of epidemiologic studies in large, community-based cohorts and measure serum AGEs in persons with diabetes in the ARIC MRI Study. To accomplish Aim 2, the candidate will undertake training in biochemistry, pathology, and anatomy, collaborate with existing studies of AGEs and work closely with clinical chemistry experts. The overarching goal of this project is to link epidemiologic research regarding hyperglycemia and CVD risk, pathologic and biochemical research on AGEs, to the development of diabetic complications. This research will provide important information regarding risk thresholds and screening for preclinical risk states in non-diabetics and help define the role of AGEs in diabetic CVD. This research may help inform the development of new therapeutic strategies to inhibit the effects of chronic hyperglycemia and prevent the progression of atherosclerosis and cardiovascular events.